SYNOPSIS OF PROGRAM: The aims of this program project are to use the mammalian reoviruses, and related viruses, to study interactions of viruses with the nervous and immune system. The program is interdisciplinary, ranging from molecular biology, immunology, and neuroanatomy, to neurobiology, all having a central focus on studies of viral-host and viral-cell interactions. The breadth of the program allows us to integrate whole animal studies with molecular and biochemical studies, thus providing us with an opportunity to relate tissue specific aspects of neurotropic viral infection with precise molecular determinants. Reoviruses are one of the best studied systems for studying the pathogenesis of neurotropic viruses and thus provide a useful framework for developing general insights into CNS viral infections. In addition studies with neurotropic viruses, such as reoviruses, provide new and unusual ways to probe neural pathways, functional subsets of neurons, communication between the immune system and the nervous system, and the nature of immunity in the CNS. The major areas to be studied are the pathogenesis of the steps in reovirus infection of the peripheral and central nervous system, the function of components of the immune system in response to reovirus infection, how reovirus interacts with the NMJ and synapse, and early events in the life cycle of two other neurotropic, enteric viruses (polio in monkeys and Theiler's virus in mice). The five participating investigators will extensively collaborate. RATIONALE FOR THE PROPOSED PROGRAM AS IT IS CONSTITUTED IN THIS RENEWAL: This program project is now entering its eleventh year. The first year of the program (1981) grew out of extensive studies, in which it became clear that the interaction of reoviruses with the nervous system was providing unique insights into aspects of the molecular basis of viral injury to the nervous system. In particular, the genetics of reovirus was useful for identifying the role of different viral genes in CNS tropism, virulence, and attenuation. A program was developed in order to broaden the scope of the studies beyond the expertise of any one individual to encompass virology, immunology, neurobiology and molecular biology.